This invention is predicated upon the discovery that tartrate-resistant acid phosphatase (TRAP) is a potent differentiating factor for osteoclasts. The invention provides, in the presently claimed embodiment, TRAP-coated bone grafts and implantable permanent orthopedic and dental prostheses.
TRAP, also known as uteroferrin (12; see the appended Citations), purple acid phosphatase (13), or type 5 acid phosphatase (14-16), is an iron-containing, cationic glycoprotein with a molecular weight of about 35 kDa. A variety of organs including bone, spleen, lung, placenta, the pregnant pig uterus and certain leukemic cells express this enzyme (12-17). TRAP enzyme activity is detected in blood and a high enzyme level reflects active bone remodeling (18,19). In bone, the enzyme is highly expressed by multinuclear osteoclasts and mononuclear cells thought to be osteoclasts or osteoclast precursors (15). The high level of expression by osteoclasts and TRAP concentration in cytoplasmic vacuoles, extracellular channels, ruffled borders and at the cell-bone interface have implicated the enzyme in bone matrix degradation (20). The function of TRAP, however, is still unknown. A blocking antibody to porcine uteroferrin markedly inhibited both the enzyme activity and bone resorption by osteoclasts in vitro (21). Several reports point to a role for TRAP in bone remodeling. Knock-out mice lacking TRAP, generated by the homologous recombination technique, showed abnormal endochondral ossification of bones and an unusual form of mild osteopetrosis (22). A number of studies have shown that M-CSF plays a critical role in both macrophage and osteoclast maturation and function (3).
Osteoclasts, the cells that resorb bone, are essential for normal skeletal growth and remodeling. They are derived from hematopoietic progenitor/stem cells of the granulocyte/macrophage lineage, but the exact point of their divergence is controversial (1,2). While recent studies have revealed several factors involved in cell-to-cell interactions in development of osteoclast function (3,4), regulation of osteoclast progenitor differentiation and recruitment to a bone surface for resorption is still poorly understood. Better understanding of the molecular mechanisms of osteoclast differentiation and recruitment could lead to novel diagnostics and therapeutics for use in the prevention and management of osteoporosis, a common disease that results from a net imbalance between bone resorption and bone formation in the adult skeleton. This imbalance can widen when resorption accelerates after menopause associated with an increase in osteoclast numbers and resorptive activity. It is also known that certain carcinomas are prone to metastasize to bone and/or can release factors locally or systemically that promote osteolysis (bone resorption). The molecular and cellular bases of such tumor properties are not fully understood.
The invention provides, in the presently claimed embodiment, a composition or device suitable for orthopedic or dental implantation to bone, characterized by tartrate-resistant acid phosphatase (TRAP) adsorbed to a porous hydroxyapatite substratum. Such implants include autologous bone grafts, cadaveric bone allografts, hydroxyapatite-containing bone cements, prosthetic devices such as artificial joints and teeth having hydroxyapatite-coated bone attachment surfaces, and orthopedic attachment devices such as staples and plates having hydroxyapatite-coated bone contacting surfaces.
Upon implantation, the TRAP coating serves to recruit or attract osteoclast progenitor cells from the bone marrow or bloodstream to the bone implant or hydroxyapatite surface of the prosthetic or attachment device. The recruited osteoclast population etches the bone mineral or hydroxyapatite surface of the implant and thereby provides the natural signals to recruit osteoblasts to lay down new bone that will abut and integrate with the graft or prosthetic surface mimicking the natural process of bone deposition on an osteoclast resorbed bone surface. The TRAP-induced stimulation of osteoclast recruitment results in osteointegration and enhanced bonding of the graft or prosthesis to the patient""s bone. This reduces recovery time from the operation and lengthens the life of implants by reducing their well-documented tendency to loosen over several years. Bone grafts also are integrated more effectively mechanically and biologically into living bone at the implant site.